Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, and cigarette smoke as well as serum cholesterol. Elevated concentrations of serum cholesterol have been demonstrated by a number of clinical studies to be a major contributing factor in the development and progression of atherosclerosis, which is characterized by the formation of cholesterol-containing plaques in the aorta and lesser arteries. In mammals, about ⅓ of the serum cholesterol is derived from exogenous dietary sources, which enters the body through absorption in the intestine, and ⅔ of the serum cholesterol are derived through endogenous de novo synthesis in the liver involving a complex set of enzyme-catalyzed reactions and regulatory mechanisms.
It has been reported in the literature that intestinal cholesterol absorption is an energy-independent, protein-mediated process rather than a passive diffusion process. Research efforts that focused on identifying classes of compounds that are able to interfere with the above-described processes have revealed that compound classes having a 2-azetidinone may be useful in lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls.
A non-exhaustive list of such azetidinones can be found in WO 93/02048, WO 94/17038, WO 95/08532, WO 95/26334, U.S. Pat. No. 5,633,246, WO 95/35277, WO 96/16037, WO 96/19450, WO 97/16455, WO 02/50027, WO 02/50060, WO 02/50068, WO 02/50090, WO 02/66464, WO 04/000803, WO 04/000804, WO 04/000805, WO 04/081002, WO 05/021495, WO 05/021497, WO 05/033100, WO 05/044256, WO 05/044256, WO 05/062824, WO 05/061451, WO 05/061452, US 20040180860, US 20040180861, US 20050267049, U.S. Pat. No. RE 37,721, WO 2006/122186, WO 2006/137782, WO 2006/137792, WO 2006/137793, WO 2006/137794, WO 2006/137796, WO 2006/137797, WO 2007/015161, WO 2007/126358, WO 2008/052658, WO 2008/123953, WO 2008/085300, WO 2008/057336.
Extensive studies on the 2-azetidinones have shown that their activity was highly dependent on the nature and configuration of the various sidechains attached to the central β-lactam motif. These findings resulted in the development of the most prominent representative of the 2-azetidinones, Ezetimibe (also known under trade names Zetia™ and Ezetrol®), which is in use as a cholesterol-lowering drug in monotherapy and in dual therapy combined with a statin.
However, there are also side effects associated with this first generation of 2-azetidinones, which may include absorption and metabolization upon administration into the pharmalogically active glucuronide (van Heek, M. et al. Br. J. Pharmacol. 2000, 129, 1748-1754) as well as as allergic reactions, e.g. rash and angiodema. More recently a higher risk of developing cancer has been reported in specific cases.
Such drawbacks may be caused by e.g. the hydrolytic instability of the 2-azetidinone ring scaffold and/or the systemic nature of some of those compounds, which typically act as a prodrug and cause effective inhibition of the uptake of cholesterol in the small intestine only after absorption and metabolization into the pharmalogically active glucuronide (van Heek, M. et al. Br. J. Pharmacol. 2000, 129, 1748-1754).
Clearly, there is still a great need for effective inhibitors of dietary cholesterol transport or uptake through the gut membrane which show minimal drug-drug interactions and off-target pharmacology and thus have an improved safety/toxicology profile.
Applicants have now found that high pharmacological activity, i.e. inhibitory activity, can be achieved by linking the pharmacophore moiety of the molecule to a novel class of side-chains which confers beneficial toxicology and pharmacologic profile to the compounds of the invention. In particular, this side-chain intends to render the resulting bioconjugate poorly bioavailable and therefore may limit the risk caused by liver exposure. Thus, the compounds of the present invention with the structural characteristics as depicted hereinafter are able to inhibit cholesterol absorption, while overcoming the above described disadvantages of compounds known in the art.